A single beta-globin gene mutation causes sickle cell anemia. Nevertheless, the exceptional phenotypic variability of this disease suggests that other genes may modulate its phenotype. We have discovered that polymorphisms in some genes were associated with discrete subphenotypes of sickle cell anemia-stroke for example-and with disease severity estimated by an integrated analysis of laboratory data and clinical subphenotypes. In some of our studies we have learned that networks of interacting gene polymorphisms or SNPs and laboratory variables can predict the likelihood of stroke in sickle cell anemia with great accuracy. Based on these results, we will extend our original candidate gene studies to genomewide association studies, supplemented, if needed, by focused studies of new candidate genes. We will begin to examine the question of whether our findings in sickle cell stroke are generalizable to stroke and cardiovascular disease in a community-based African American population using the Jackson Heart Study, a population-based study, as a source of patient data and DNA samples. We will examine gene expression in mononuclear cells and blood outgrowth endothelial cells from patients with sickle cell pulmonary hypertension and controls, in studies founded on our observations that inflammation and genes of the TGF-beta/BMP pathway seem to be associated with several disease subphenotypes. Finally, we will examine whether the serum proteome and oxidatively modified proteins in plasma are associated with sickle pulmonary hypertension. This work is focused on answering the following gaps in understanding of the genetic modulation of sickle cell disease: what additional genes are associated with HbSS subphenotypes and how do these genes interact?;can our observations in sickle cell stroke be extended to other African Americans and inform our understanding of cardiovascular disease in this population?;is the phenotype of sickle cell pulmonary hypertension associated with differential gene expression in endothelial and mononuclear cells and is this reflected by changes in plasma proteins? In all of our studies we will apply state-of-the-art methods, some developed by our investigator team, for genotyping, gene expression, proteomics and data analysis. Progressing from genome-based studies, through gene expression, to the serum proteome, these integrated genomic studies will further illuminate our understanding of the pathophysiology and genetic modulation of sickle cell disease and bring us closer to our ultimate goal of discovering new therapeutic targets.